Towards the synthesis of histone deacetylase inhibitors based on the depsipeptide FK228

Abstract

Histones are proteins that are used as a scaffold for DNA to wrap around and on these proteins are lysines. Histone Deacetylases (HDACs) are metalloenzymes that remove acetyl groups from lysines on histones and thus cause genetic material to wrap tighter which can stop transcription. If the genes that can regulate tumour activity are affected by this method, then these are rendered inactive. In cancer patients, it can be seen that the amount of HDACs are higher than normal then in a normal person and this has created the need to understand these and find products that can inhibit these. The search for inhibitors have led to such products as SAHA, FK228 and spiruchostatins (both of the latter are depsipeptides with disulfide bridges) and by researching depsipeptides such as FK228, more understanding can be made in how these compounds work. Depsipeptides such as FK228 consist of from three components, a zinc binding thiol, which is the active site, a 'cap', which is the macrocycle and a linker that connects the two. This research shows how attempts at modifying key components, such as the linker length and saturation and the 'cap' structure of the depsipeptides have been made.

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